This soft tissue tumor is most common in the skin and subcutaneous tissue
but it has been reported in many organ systems. Its most common presentation
is a solitary small nodule. Although once thought to be derived from smooth
muscle, pathologists have now correctly identified its origin from peripheral
nerve.

A 57-year-old woman presented with a 2-year history of a palpable mass
in the upper inner quadrant of the right breast.

A 1.1-cm, poorly circumscribed, firm tumor nodule was noted, consisting
of 2 histologically distinct lesions in the same location, with some
areas showing purely well-differentiated invasive ductal carcinoma and
others composed of granular cell tumor. In 1 area, the 2 tumors collided
and infiltrated each other. The invasive ductal carcinoma was admixed
with ductal carcinoma in situ of solid and cribriform types.

To our knowledge, this is the first case report demonstrating colocalization
of these 2 neoplasms, which raises questions regarding causal relationship.
We also review the literature on granular cell tumor of the breast.

Granular cell tumors (GCT) are uncommon benign neoplasms that have
a predilection for the head and neck region. These tumors can frequently
be associated with pseudoepitheliomatous hyperplasia (PEH), which in
turn may be mistaken for squamous cell carcinoma. Although epidermal
growth factors are overexpressed in squamous cell carcinomas of the
head and neck, their presence in PEH, especially its relation to GCT,
is unknown.

We hypothesize that the expression of epidermal growth factor receptor
(EGFR), epidermal growth factor (EGF), and transforming growth factor
alpha (TGFalpha) in GCT have a role in the development of PEH overlying
some GCT. Sections from 13 cases of GCT (five with overlying PEH) were
examined histologically and evaluated immunohistochemically using monoclonal
antibodies for EGFR, EGF, and TGFalpha. These were compared with nine
cases of PEH independent of GCT. Two of five GCT with overlying PEH
and two of six GCT without overlying PEH stained positively for TGFalpha.
None of the GCT stained with EGFR or EGF. All cases of PEH, whether
or not associated with GCT, were reactive for EGFR and EGF. Four of
the five cases of PEH overlying GCT stained with TGFalpha. The staining
pattern and intensity of all three antibodies were comparable to that
of the adjacent normal squamous mucosa.

Among the three antibodies, only TGFalpha in GCT appears to be related
to the development of PEH. Epidermal growth factor receptor and EGF
do not seem to be directly involved. The reason of PEH formation associated
with GCT in the absence of growth factors is unknown.

Granular cell tumor (GCT) of the lung is a rare neoplasm comprising 6-10% of all GCT. Since it was first described in the bronchus by Kramer in 1939, less than 80 cases have been reported.

We present the clinicopathologic features of 23 GCT from 20 patients. The patients ranged in age from 20 to 57 years (median, 45 years) and included 10 males and 10 females. Of the 19 patients with available histories, nine (47%) were incidental findigns and 10 (53%) had obstructive symptoms [pneumonia, 7 (37%); atelectasis, 3 (16%)]. Three (16%) had hemoptysis, and one (5%) had weight loss. The GCT were solitary in 15 patients (75%) and multiple in five others (25%). One patient had three endobronchial lesions, and another had one endobronchial and one peripheral pulmonary lesion. Three of the patients had multiple cutaneous GCT (15%).

Grossly, they were polypoid or nodular, tan-yellow, and firm. Histologically, the endobronchial GCT consisted of submucosal infiltrates of round to oval cells with abundant granular cytoplasm. The tumor often infiltrated into peribronchial tissue and in one case focally infiltrated an adjacent lymph node. Hyalinized thickening of the subepithelial basement membrane was common; the overlying epithelium often showed squamous metaplasia or ulceration.

In those patients with available follow-up, the clinical behavior of lung GCT was benign. Our experience supports a conservative approach to therapy in most cases unless there has been extensive postobstructive lung injury. Potential conservative therapeutic approaches include bronchoscopic extirpation, laser therapy, or sleeve resection. The histogenesis of GCT is not known, although most studies suggest a peripheral nerve sheath origin. Our immunohistochemical results with positive staining for antibodies to S100 (4/4), NSE (3/3), vimentin (4/4), and actin (4/4, focal) are consistent with this concept.

Hilar pulmonary granular cell tumor: a case report and review of the literature.

Al-Ghamdi AM, Flint JD, Muller NL, Stewart KC.

Department of Pathology, Vancouver General Hospital and University of British Columbia, Canada.

Ann Diagn Pathol 2000 Aug;4(4):245-51 Abstract quote

We present a case of pulmonary granular cell tumor (GCT). A 35-year-old man underwent pulmonary resection for metastatic testicular mixed germ cell tumor when two interlobar lymph nodes were found to be enlarged and abnormal. Intraoperative frozen section examination showed their involvement by GCT.

Histologic examination of the lobectomy specimen showed a benign, predominantly hilar GCT as well as metastatic germ cell tumor.

This location, with no endobronchial component and with extension into regional hilar lymph nodes, is unusual. The differential diagnosis and the association with the metastatic testicular cancer are discussed and the literature on pulmonary GCT is reviewed.

Persistent atelectasis and recurrent pneumonia in the same location should raise suspicion of congenital anomalies or obstructing lesions of the bronchus leading to the affected area.

We present an 8-year-old black female with a history of recurrent fever, cough, atelectasis of the right middle and lower lobes, and weight loss for several months. Flexible bronchoscopy revealed a polypoid mass obstructing the bronchus intermedius. Biopsy of the neoplasm demonstrated a granular cell tumor (GCT).

The patient had a lobectomy of the right lower and middle lobes. She had no recurrence of the tumor after several years of follow-up.

Pulmonary granular cell tumor coexisting with bronchogenic carcinoma.

Cutlan RT, Eltorky M.

Department of Pathology, University of Tennessee, Memphis, TN 38163, USA.

Ann Diagn Pathol 2001 Apr;5(2):74-9 Abstract quote

Pulmonary granular cell tumors (GCTs) are uncommon and predominantly benign. The coexistence of GCTs with bronchogenic carcinoma is rare.

We report three cases of GCT occurring simultaneously with a primary bronchogenic carcinoma. In one case mucoepidermoid carcinoma was seen colliding with a bronchial submucosal GCT. In another case an endobronchial GCT was seen beneath squamous cell carcinoma in situ and adjacent to invasive squamous carcinoma. In the third case a central bronchial GCT was identified concurrently with a peripheral adenocarcinoma.

We suggest that the presence of a GCT should prompt adequate sampling to rule out the coexistence of bronchogenic carcinoma. Clinical awareness and complete evaluation for a malignant primary lung tumor will lead to more appropriate therapy.

Summary The occurrence of granular cell tumor (GCT) in penile tissue is very rare, with only 9 examples reported to date in the English-language literature.

Herein, we describe the clinicopathologic and immunohistochemical findings in 9 additional cases. The patients ranged in age from 20 to 60 years (mean, 42 years; median, 40 years) at time of diagnosis. All penile tumors were solitary and arose in the dermis of the penile shaft (n = 4), prepuce (n = 3), and corona (n = 2). A patient had a history of multiple cutaneous GCTs. Duration of symptoms before surgery ranged from 5 days to 2 years with the presence of an asymptomatic nodule representing the most common tumor-related complaint (n = 8). The lesions ranged in size from 0.6 to 2.5 cm (mean, 1.5 cm; median, 1.5 cm).

Benign GCT involving superficial soft tissue of the penis can be adequately managed by a simple excision. Patients with microscopically involved surgical margins can be clinically followed without immediate additional surgery.

Malignant granular cell tumor closely associated with the radial nerve
in the left upper arm, was found in a 34-year old man.

The tumor increased rapidly in size, was locally invasive and showed
recurrence and metastases to lymph nodes and the lungs. The tumor was
composed solely of granular cells and its histological features were
very similar to those of benign granular cell tumors. However, considerable
variation of cellular size and shape, hyperchromatic plump nuclei, and
some disordered cellular arrangement were thought to be significant
indications of malignancy.

Ultrastructural study of the tumor revealed many lysosome-like dense
granules in the cytoplasm. The presence of a few axon-like cytoplasmic
processes between granular cells and the intimate anatomical association
of the tumor with the radial nerve seemed to support the concept of
peripheral nerve origin of the malignant granular cell tumor.

ORAL CAVITY

SKIN

Multiple cutaneous granular cell tumors in a child
in remission for Hodgkin's disease.

Multiple cutaneous granular cell tumors are uncommon among children.
We describe a 13-year-old boy with Hodgkin's disease in remission for
3 years who had multiple cutaneous granular cell tumors.

We wondered whether this association was real or a coincidence and
whether this child was at increased risk of development of malignant
granular cell tumors.

URINARY BLADDER

VULVA

Granular cell tumors of the vulva.

Majmudar B, Castellano PZ, Wilson RW, Siegel RJ.

Department of Pathology, Emory University School of Medicine, Atlanta,
Georgia.

J Reprod Med 1990 Nov;35(11):1008-14 Abstract quote

Granular cell tumor (GCT), although nearly ubiquitous, is seen infrequently
in the vulva. A review of the surgical pathology files from Grady Memorial
Hospital, Atlanta, Georgia, from 1983 through 1987 identified eight
cases of vulvar GCT.

Five of the eight patients had more than one skin and soft tissue lesion.
Two of the five had biopsy-proven multicentric GCT with a unique clinical
course. One of the patients was a 32-year-old woman with multiple vulvar,
lingual, laryngeal, bronchial and pulmonary GCT, necessitating multiple
excisions and ultimately pneumonectomy. The second patient had multiple
GCTs in the vulva and inguinal area and finally in both lungs, resulting
in her death at age 39.

No dependable microscopic features could be identified to distinguish
benign GCT from its more aggressive variant. However, Feulgen DNA histomorphometry
demonstrated aneuploidy in the patient with apparent lung metastases,
whereas the tumors from patients with a benign course as well as from
the patient with multiorgan involvement were diploid.

In three of five patients who could be interviewed there was a history
of soft tissue tumors in members of the family. The multifocal nature
and possible familial component of GCT need to be explored further.

Background: Cutaneous granular cell tumor (GCT) may present with extension into the junctional region of the epidermis and thus may mimic melanocytic neoplasms.

Methods: We reviewed three cases of cutaneous GCT where a melanocytic neoplasm was either initially diagnosed or considered in the differential diagnosis. Histopathology was evaluated in regards to features associated with melanocytic neoplasms. Immunohistochemistry was performed to delineate a panel useful in the distinction of these and other entities.

Results: All cases consisted of spindle and epithelioid cells with granular cytoplasm and bland nuclei and were centered in the superficial dermis with extension into the epidermis. Two cases resembled Spitz nevi and one case demonstrated lentiginous growth. All cases stained positively with calretinin and inhibin. Two of the three cases stained diffusely with S100 and 2/2 cases with CD56. HAM56 and CD68 were positive in one case and another showed positivity for NSE and PGP9.5. HMB-45, tyrosinase, and Melan-A were non-reactive in all cases tested.

Conclusions: GCT may involve the epidermis and has a growth pattern similar to melanocytic neoplasms. An immunohistochemical (IHC) panel including S100, Melan-A, tyrosinase, HMB-45, CD56, CD68, calretinin, inhibin, and PGP9.5 may aid in the distinction and may spare the patient from unnecessary morbidity.

Clinically described as smooth, nontender cutaneous nodules, the tumors ranged in size from 0.2 to 2.8 cm (median, 0.8 cm) and were present from months to years before excision. Mitoses numbered from 1 to 6 per mm (median, 2). Eight of the lesions were polypoid, based in the papillary dermis with extension to the superficial dermis and associated with an epithelial collarette. Five of the lesions were situated deeper in the reticular dermis with limited extension into the subcutis but clinically were also nodular. All the tumors were well circumscribed and composed of spindled to ovoid cells with abundant granular, eosinophilic cytoplasm and vesicular nuclei with small prominent nucleoli.

Immunohistochemistry revealed reactivity only for NKI-C3 (11 of 12 cases), CD68 (7 of 11 cases), and NSE (5 of 10 cases); S-100 protein as well as other melanocytic, epithelial, and myoid markers were uniformly negative. All 13 of the lesions were locally excised and in the 8 cases with adequate follow-up ranging from 13 to 126 months (mean, 68 months; median, 41 months), none has recurred locally. However, one tumor (case no. 11) gave rise to a local lymph node metastasis 25 months after presentation, but the patient is currently disease-free 70 months after lymphadenectomy.

These cutaneous granular tumors do not appear to be neural or Schwannian in nature, but their precise line of differentiation is unknown.

Department of Pathology, University of California, San Francisco
94143-0506.

Am J Surg Pathol 1991 Jan;15(1):48-58 Abstract quote

Most cutaneous and noncutaneous granular-cell tumors are currently
thought to be of Schwann-cell derivation.

We present seven unusual cutaneous granular-cell lesions in which Schwann-cell
origin can be excluded or is inapparent. Four of these lesions are of
a previously undescribed type, and, unlike conventional granular-cell
tumors of the skin, show a polypoid configuration, numerous mitoses,
cytologic atypia, and a primitive immunophenotype.

We propose the term "primitive polypoid granular-cell tumor" for these
lesions. One occurred in a child, and three in adults. There have been
no metastases to date, with follow-up periods of 2, 4, 4, and 16 years,
respectively, although one tumor recurred locally. Additional cases
and longer follow-up may be required to rule out the possibility that
primitive polypoid granular-cell tumor is a low-grade malignancy. Two
other granular-cell lesions represent variants of leiomyosarcoma, one
of which widely metastasized. The last case is a granular-cell form
of nodular basal-cell carcinoma.

Cutaneous granular-cell neoplasms can show varying differentiation
and behavior. Pathologists should not equate the occurrence of cytoplasmic
granularity in a cutaneous neoplasm with the diagnosis of granular-cell
schwannoma.

Department of Pathology, Penn State University College of Medicine, Hershey, Pa, USA.

Arch Pathol Lab Med. 2004 Jul;128(7):771-5. Abstract quote

CONTEXT: Granular cell tumor (GCT) is a rare tumor of nerve sheath origin with a predilection for upper aerodigestive tract, skin, and soft tissue. The neoplastic cells typically express S100 and CD68 (KP-1), the latter due to cytoplasmic lysosome content. However, the histogenesis of this tumor is unknown. Additionally, distinction between benign and malignant GCT is difficult because of histologic similarity and lack of reliable criteria that can predict clinical behavior.

OBJECTIVE: To perform a comparative, side-by-side immunohistochemical assessment of the traditional immunohistochemical markers for GCTs (S100, CD68), along with the newer markers (inhibin-alpha, protein gene product 9.5) for these tumors.

RESULTS: Twenty-seven of 27 primary GCTs and 1 of 3 recurrent GCTs had typical histologic features, while the 2 consecutive recurrent GCT specimens from the same patient were atypical (moderate nuclear atypia and prominent nucleoli alone). The mean age for primary GCT was 37.3 years (range, 5-67 years), and mean size was 1.89 cm. None of the cases metastasized. All 30 specimens showed diffuse (2+ to 3+) staining for S100, CD68, and inhibin-alpha, and 3+ staining for protein gene product 9.5; pseudoepitheliomatous hyperplasia was nonreactive. The Ki-67 proliferative index was less than 1% to 20% in typical nonrecurrent cases, 1% in the typical recurrent case, and 1% and 10% in 2 sequential recurrences of the atypical case.

CONCLUSION: Our study expands the immunophenotype of GCT (S100, CD68, protein gene product 9.5, and inhibin-alpha) regardless of location and supports a neural origin. Intensity of immunohistochemical staining had no prognostic significance. Although 1 of the 2 recurrent GCTs had atypical features, the Ki-67 proliferative index did not distinguish reliably between typical (nonrecurrent) and atypical or recurrent GCTs. The significance of inhibin expression with regard to cell differentiation and pathogenesis is unclear and warrants further investigation.

In alveolar soft part sarcomas, some of the tumor cells were positive
for desmin, but negative for nervous tissue markers. The tumor cells
of granular cell tumors were stained with anti-S-100 protein antibody,
but not with anti-neuron-specific enolase antibody. In contrast, the
tumor cells of paragangliomas were positive for neuron-specific enolase,
but not for S-100 protein except for stellate cells surrounding the
tumor cell nests. This immunohistochemical approach was valuable for
the differential diagnosis of these three tumors. Furthermore, the complete
absence of cytokeratin in all of the tumor cells may be helpful in distinguishing
these three tumors from metastatic carcinoma in soft tissue. The histogenesis
of alveolar soft part sarcoma is a matter of controversy.

The result that besides desmin actin was also demonstrated in some
of the tumor cells may support the myogenic origin of this tumor.

Expression of Inhibin- by Granular Cell Tumors of the Gallbladder
and Extrahepatic Bile Ducts

This is the first report of inhibin- expression in granular cell tumors.

A Medline search of the literature revealed no case reports of granular
cell tumors in any location of the body being tested for inhibin- immunohistochemically,
by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation.
Seventeen cases of previously diagnosed granular cell tumors of the
gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained
sections, and S-100 protein immunostain were retrieved from the archives
of the Armed Forces Institute of Pathology.

All cases were reviewed for diagnostic accuracy and then immunostained
for inhibin- (with endogenous biotin blocking). All 17 (100%) cases
were diffusely positive for inhibin- immunostain. Previous studies of
inhibin--positive lesions reported in the literature include sex cord
stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell
tumors), placental and gestational trophoblastic lesions, and adrenal
cortical tumors. This study adds the granular cell tumor to the list
of inhibin-positive lesions and should prove helpful in differential
diagnosis of these lesions.

Department of Pathology, University of Pavia and
I.R.C.C.S. S. Matteo Hospital, Pavia, Italy.

Arch Pathol Lab Med 2000 May;124(5):709-11 Abstract quote

BACKGROUND: Granular cell changes can be observed in a variety of benign
and malignant tumors, and are seen more commonly in granular cell tumors,
which in about 5% of cases develop in the breast. Granular cells also
have been observed in sites of previous trauma, such as surgery, and
are found to be inflammatory reactions of histiocytic origin.

METHODS AND RESULTS: We investigated, morphologically and immunohistochemically,
2 granular cell lesions occurring in mastectomy scars after surgery
for carcinoma. Both lesions were composed of strands and nests of large
granular cells, haphazardly set in a background of fibrous tissue, with
sparse inflammatory infiltrates. Several tortuous hypertrophic nerve
bundles were also embedded in the fibrous tissue. A few of these nerve
bundles showed degenerative changes and contained granular cells. Immunohistochemically,
granular cells were positive for S100 protein, neuron-specific enolase,
vimentin, and CD68 antigen.

CONCLUSIONS: We consider these proliferative lesions of peripheral
nerves to have the features of both granular cell tumor and traumatic
neuroma. These cases indicate that traumatic neuroma can undergo extensive
granular cell changes and constitute a previously unrecognized entity,
which we provisionally label granular cell traumatic neuroma. Granular
cell traumatic neuroma has to be taken into consideration when evaluating
lesions occurring at mastectomy scars and should be differentiated from
malignant tumors with granular cells, such as apocrine carcinoma and
alveolar soft part sarcoma.

MELANOMA

HMB-45 and Melan-A are Useful in the Differential Diagnosis Between Granular Cell Tumor and Malignant Melanoma.

Granular cell tumors (GCTs), especially if atypical or malignant, may share cytomorphologic and architectural features with malignant melanoma, when the latter shows granular cell change. In many cases, these neoplasms can be differentiated from each other on histologic grounds, but distinction may sometimes be challenging. By immunohistochemistry, both tumors are strongly positive for S-100 protein and frequently express other nonspecific markers such as CD68, NSE, and NKIC3.

In the current study, we reviewed 60 cases of conventional cutaneous, mucosal, and visceral GCT and studied the use of immunoperoxidase staining for the differential diagnosis between malignant melanoma and GCT. Immunohistochemical stains for S-100 protein, A, HMB-45, and microphthalmia transcription factor (MITF) were performed in all cases. All of the tumors were positive for S-100 protein. MITF immunostaining was diffusely positive in 53 (88%) cases, focally positive in three (5%) cases, and negative in four (7%). Fifty-seven (95%) tumors were negative for Melan-A, one case was focally positive, and two cases showed rare positive tumor cells. None of the tumors expressed HMB-45.

In conclusion, GCT and malignant melanoma can be reliably differentiated on the basis of immunohistochemical stains in the majority of cases. Although not always positive in malignant melanoma, in this context, HMB-45 expression seems to be 100% specific for the diagnosis of melanoma. Melan-A is slightly less specific, with rare cases of GCT showing focal positivity. MITF is not useful in this differential-93% of the GCTs in our series showed nuclear reactivity for this marker. The latter finding highlights the limited specificity of this antibody in the diagnosis of melanocytic tumors.

METASTATIC BREAST CANCER

Metastatic breast carcinoma mimicking granular cell tumor.

Franzblau MJ, Manwaring M, Plumhof C, Listrom MB, Burgdorf WH.

Marin General Hospital, San Rafael, California.

J Cutan Pathol 1989 Aug;16(4):218-21 Abstract quote

Metastatic breast carcinoma may assume many patterns. We describe a
case in which cutaneous, pulmonary and lymph node metastases of an adenocarcinoma
of the breast all resembled granular cell tumor.

In all sites, the lesion stained positive with antibodies against EMA
and cytokeratins, but failed to stain with anti-S100.

PROGNOSIS AND TREATMENT

CHARACTERIZATON

PROGNOSIS

Malignant granular cell tumor metastatic to the orbit.

Callejo SA, Kronish JW, Decker SJ, Cohen GR, Rosa RH Jr.

Bascom Palmer Eye Institute, University of Miami School of Medicine,
Florida 33101, USA.

Ophthalmology 2000 Mar;107(3):550-4 Abstract quote

OBJECTIVE: Malignant granular cell tumor is a rare type of soft tissue
sarcoma. To our knowledge, ocular (eyelid) involvement has been described
in only two cases. Herein, we report the clinicopathologic features
of an unusual case of malignant granular cell tumor metastatic to the
orbit.

DESIGN: Observational case report.

METHODS: Retrospective review of the medical record and the histopathologic
and electron microscopic findings and review of the literature.

RESULTS: A 72-year-old man with biopsy-proven granular cell tumor in
the cervical region was initially seen with proptosis and motility disturbance.
A magnetic resonance imaging scan showed a large intraconal mass, and
biopsy of the orbital mass revealed granular cell tumor. Histopathologic
examination of the primary neck tumor and the orbital mass revealed
increased nuclear atypia and pleomorphism in the consecutive lesions.
The morphologic impression of granular cell tumor was also supported
by the immunohistochemical demonstration of S-100 protein expression
and ultrastructural findings typical of granular cell tumor. Six months
after the orbital involvement, systemic workup revealed multiple apparent
bony and lung metastases.

CONCLUSIONS: We report the first malignant granular cell tumor metastatic
to the orbit and suggest the inclusion of this tumor in the differential
diagnosis of metastatic orbital lesions.